Screening for the Human Immunodeficiency Virus (HIV) Infection

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The Centers for Medicare and Medicaid Services (CMS) has determined that the evidence is adequate to conclude that screening for HIV infection, which is recommended with a grade of A by the U.S. Preventive Services Task Force (USPSTF) for certain individuals, is reasonable and necessary for early detection of HIV and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B. Therefore CMS will cover both standard and U.S. Food and Drug Administration (FDA)-approved HIV rapid screening tests for: Annual voluntary HIV screening of Medicare beneficiaries at increased risk for HIV infection per USPSTF guidelines: Men who have had sex with men after 1975; Men and women having unprotected sex with multiple [more than one] partners; Past or present injection drug users; Men and women who exchange sex for money or drugs, or have sex partners who do; Individuals whose past or present sex partners were HIV-infected, bisexual or injection drug users; Persons being treated for sexually transmitted diseases; Persons with a history of blood transfusion between 1978 and 1985; Persons who request an HIV test despite reporting no individual risk factors, since this group is likely to include individuals not willing to disclose high-risk behaviors; and Voluntary HIV screening of pregnant Medicare beneficiaries when the diagnosis of pregnancy is known, during the third trimester, and at labor. We are deleting the following reference to non-coverage of HIV screening from the coverage manual, Section 190.14: "However, in the absence of a documented AIDS defining or HIV-associated disease, an HIV-associated sign or symptom, or documented exposure to a known HIV-infected source, the testing is considered by Medicare to be screening and thus is not covered by Medicare (for example, history of multiple blood component transfusions, exposure to blood or body fluids not resulting in consideration of therapy, history of transplant, history of illicit drug use, multiple sexual partners, same-sex encounters, prostitution, or contact with prostitutes)."

Decision Memo: To: Administrative File: CAG-00409N From: Louis B. Jacques, MD Director, Coverage and Analysis Group Tamara Syrek Jensen, JD Deputy Director, Coverage and Analysis Group Marcel E. Salive, MD, MPH Director, Division of Medical and Surgical Services William Larson, MA Lead Analyst Lawrence Schott, MD, MS Lead Medical Officer Subject: Coverage Decision Memorandum for Screening for the Human Immunodeficiency Virus (HIV) Infection Date: December 8, 2009 I. Decision The Centers for Medicare and Medicaid Services (CMS) has determined that the evidence is adequate to conclude that screening for HIV infection, which is recommended with a grade of A by the U.S. Preventive Services Task Force (USPSTF) for certain individuals, is reasonable and necessary for early detection of HIV and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B. Therefore CMS will cover both standard and U.S. Food and Drug Administration (FDA)-approved HIV rapid screening tests for: Annual voluntary HIV screening of Medicare beneficiaries at increased risk for HIV infection per USPSTF guidelines: Men who have had sex with men after 1975; Men and women having unprotected sex with multiple [more than one] partners; Past or present injection drug users; Men and women who exchange sex for money or drugs, or have sex partners who do; Individuals whose past or present sex partners were HIV-infected, bisexual or injection drug users; Persons being treated for sexually transmitted diseases; Persons with a history of blood transfusion between 1978 and 1985; Persons who request an HIV test despite reporting no individual risk factors, since this group is likely to include individuals not willing to disclose high-risk behaviors; and Voluntary HIV screening of pregnant Medicare beneficiaries when the diagnosis of pregnancy is known, during the third trimester, and at labor. We are deleting the following reference to non-coverage of HIV screening from the coverage manual, Section 190.14: "However, in the absence of a documented AIDS defining or HIV-associated disease, an HIV-associated sign or symptom, or documented exposure to a known HIV-infected source, the testing is considered by Medicare to be screening and thus is not covered by Medicare (for example, history of multiple blood component transfusions, exposure to blood or body fluids not resulting in consideration of therapy, history of transplant, history of illicit drug use, multiple sexual partners, same-sex encounters, prostitution, or contact with prostitutes)." II. Background Infection with HIV is a continuing worldwide pandemic described by the World Health Organization as "the most serious infectious disease challenge to global public health". 1 , 2 Acquired immunodeficiency syndrome (AIDS) is diagnosed when an HIV-infected person’s immune system becomes severely compromised and/or a person becomes ill with an HIV-related opportunistic infection. 3 , 4 Without treatment, AIDS usually develops within 8-10 years after a person’s initial HIV infection. While there is presently no cure for HIV, an infected individual can be recognized by screening; and subsequent access to skilled care plus vigilant monitoring and adherence to continuous antiretroviral therapy (ART) may delay the onset of AIDS and increase quality of life for many years. Significantly, more than half of new HIV infections are estimated to be sexually transmitted from infected individuals who are unaware of their HIV status. 5 Consequently, improved secondary disease prevention and wider availability of screening linked to HIV care and treatment would not only delay disease progression and complications in untested or unaware older individuals, but could also decrease the spread of disease to those living with or partnered with HIV-infected individuals. Despite such intentions, however, whether due an overall lack of understanding of HIV/AIDS, individuals’ reluctance to disclose high-risk behaviors – or physicians’ competing priorities and lack of reimbursement 6 – current risk-based screening methods based upon known or suspected HIV exposure still fail to identify a large percentage of infected individuals. In the U.S., for example, there are estimated to be more than one million persons living with HIV, including more than a quarter million who remain undiagnosed. 7 , 8 When a life-threatening infectious disease without an effective vaccine, such as HIV, cannot be primarily prevented via combined behavioral strategies 9 and educational interventions, wider availability of screening – preliminary testing for persons without apparent signs and symptoms of the infection – may be the next best preventive strategy. From an epidemiological perspective, HIV infection disproportionately impacts identifiable racial, gender and ethnic groups, and thus requires sensitivity to cultural and linguistic barriers to screening and access to medical care. By transmission category, while a growing proportion of HIV infections are now attributed to heterosexually acquired infections in women and persons of color, men who have sex with men remain the most affected group in the U.S., accounting for about half of Americans living with HIV. Globally, however, most HIV infections now result from heterosexual transmission; and most HIV infections in U.S. women are heterosexually acquired, including a 4.1% increase per year between 1999 and 2004 among women older than 60 years of age. 10 Until 2007, there were no comprehensive, population-based data informing physicians about the well-being, sexual norms and sexual problems of older, community-dwelling Americans. Based on representative data from the National Social Life, Health, and Aging Project (NSHAP), it is now known that a majority of older adults regard sexuality as an important part of life and that many are sexually active, including 53% among those respondents 65-74 years of age and 26% among respondents 75 -85 years of age. Overall, only 38% of men and 22% of women in the NSHAP survey reported having discussed sex with a physician since 50 years of age; thus much high-risk behavior may go unrecognized. Frequent reasons noted for such poor communication included unwillingness of older patients and their physicians to initiate such discussions, sex and age differences between patients and physicians, as well as individual and societal attitudes inhibiting discussion about sexuality at older ages. 11 In March 2009, based upon new authority to cover additional preventive services for Medicare beneficiaries and the publication of updated HIV screening guidelines, CMS initiated this national coverage analysis to evaluate the existing evidence on HIV screening and determine if the body of evidence is sufficient for Medicare coverage. Except to make a conforming change about HIV screening in NCD 190.14, this analysis does not address the use of HIV antibody testing as a diagnostic test (for example, confirmatory western blot or immunofluorescent assay in a seropositive patient), but rather focuses on the balance of benefits and harms, individually as well as from the public health perspective, of screening for HIV infection. III. History of Medicare Coverage Over the past 25 years, Congress added coverage of specific preventive and screening services to the voluntary Medicare Part B program, e.g., Pap smear, screening pelvic exams, screening mammography, colorectal cancer screening tests and diabetes screening tests. Effective January 1, 2009, under Section 101(a) of the Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) (Public Law 110-275), CMS may add coverage of "additional preventive services" if certain statutory requirements are met. 12 Under our rules implementing this statute, 42 CFR 410.64, this benefit allows the coverage of preventive services not otherwise described in Title XVIII of the Act. 13 Specifically, this regulation provides: §410.64 Additional preventive services (a) Medicare Part B pays for additional preventive services not otherwise described in this subpart that identify medical conditions or risk factors for individuals if the Secretary determines through the national coverage determination process (as defined in section 1869(f)(1)(B) of the Act) that these services are all of the following: (1) Reasonable and necessary for the prevention or early detection of illness or disability. (2) Recommended with a grade of A or B by the United States Preventive Services Task Force. (3) Appropriate for individuals entitled to benefits under part A or enrolled under Part B. (b) In making determinations under paragraph (a) of this section regarding the coverage of a new preventive service, the Secretary may conduct an assessment of the relation between predicted outcomes and the expenditures for such services and may take into account the results of such an assessment in making such national coverage determinations. 14 IV. Timeline of Recent Activities Date Action March 12, 2009 CMS initiates this national coverage analysis for screening for the HIV infection. April 13, 2009 Initial 30-day public comment period closed. September 9, 2009 Proposed decision memorandum posted; 30-day comment period begins. V. FDA Status HIV antibody testing first became available in 1985. These commonly used, FDA-approved HIV antibody screening tests – using serum or plasma from a blood draw – are known as EIA (enzyme immunoassay) or ELISA (enzyme-linked immunosorbent assay) tests. Laboratory results of EIA or ELISA antibody tests may not be available for a week or more. Developed for point-of-care testing using alternative samples, six rapid HIV-1 and/or HIV-2 antibody tests – using fluid obtained from the oral cavity or using whole blood, serum or plasma from a blood draw or finger stick – were approved by the FDA from 2002-2006. 15 , 16 Results can be available within approximately 20 minutes. VI. General Methodological Principles When making national coverage determinations concerning additional preventive services, CMS applies the statutory criteria in §1861(ddd) of the Social Security Act and evaluates relevant clinical evidence to determine whether or not the service is reasonable and necessary for the prevention or early detection of illness or disability, is recommended with a grade of A or B by the USPSTF, and is appropriate for individuals entitled to benefits under part A or enrolled under Part B of the Medicare program. Public comments sometimes cite published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments that contain personal health information will not be made available to the public. CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. VII. Evidence A. Introduction Consistent with §1861 (ddd)(1)(A) and 42 CFR 410.64(a)(1), additional preventive services must be reasonable and necessary for the prevention or early detection of illness or disability. With respect to evaluating whether screening tests conducted on asymptomatic individuals are reasonable and necessary, the analytic framework involves consideration of different factors compared to either diagnostic tests or therapeutic interventions. Evaluation of screening tests has been largely standardized in the medical and scientific communities, and the "value of a screening test may be assessed according to the following criteria: Simplicity . In many screening programmes more than one test is used to detect one disease, and in a multiphasic programme the individual will be subjected to a number of tests within a short space of time. It is therefore essential that the tests used should be easy to administer and should be capable of use by para-medical and other personnel. Acceptability . As screening is in most instances voluntary and a high rate of co-operation is necessary in an efficient screening programme, it is important that tests should be acceptable to the subjects. Accuracy . The test should give a true measurement of the attribute under investigation. Cost . The expense of screening should be considered in relation to the benefits resulting from the early detection of disease, i.e., the severity of the disease, the advantages of treatment at an early stage and the probability of cure. Precision (sometimes called repeatability) . The test should give consistent results in repeated trials. Sensitivity . This may be defined as the ability of the test to give a positive finding when the individual screened has the disease or abnormality under investigation. Specificity . This may be defined as the ability of the test to give a negative finding when the individual screened does not have the disease or abnormality under investigation." 17 As Cochrane and Holland (1971) further noted, evidence on health outcomes, i.e., "evidence that screening can alter the natural history of disease in a significant proportion of those screened", is important in the consideration of screening tests since individuals are asymptomatic and "the practitioner initiates screening procedures". The USPSTF has also integrated consideration of these factors in their assessments and recommendations. B. United States Preventive Services Task Force (USPSTF) Recommendations 2007 According to the USPSTF, individual high-risk behaviors or those individuals at increased risk (as determined by prevalence rates) include: Men who have had sex with men after 1975 Men and women having unprotected sex with multiple partners Past or present injection drug users Men and women who exchange sex for money or drugs, or have sex partners who do Individuals whose past or present sex partners were HIV-infected, bisexual or injection drug users Persons being treated for sexually transmitted diseases Persons with a history of blood transfusion between 1978 and 1985 Persons who request an HIV test despite reporting no individual risk factors, since this group is likely to include individuals not willing to disclose high-risk behaviors 18 USPSTF Summary of Recommendations on Screening for HIV (2007): "The U.S. Preventive Services Task Force (USPSTF) strongly recommends that clinicians screen for human immunodeficiency virus (HIV) all adolescents and adults at increased risk for HIV infection. Rating: ‘A’ Recommendation 19 Rationale : The USPSTF found good evidence that both standard and U.S. Food and Drug Administration (FDA)-approved rapid screening tests accurately detect HIV infection. The USPSTF also found good evidence that appropriately timed interventions, particularly highly active antiretroviral therapy (HAART), lead to improved health outcomes for many of those screened, including reduced risk for clinical progression and reduced mortality. Since false-positive test results are rare, harms associated with HIV screening are minimal. Potential harms of true-positive test results include increased anxiety, labeling, and effects on close relationships. Most adverse events associated with HAART, including metabolic disturbances associated with an increased risk for cardiovascular events, may be ameliorated by changes in regimen or appropriate treatment. The USPSTF concluded that the benefits of screening individuals at increased risk substantially outweigh potential harms." "The USPSTF makes no recommendation for or against routinely screening for HIV adolescents and adults who are not at increased risk for HIV infection. Rating: ‘C’ Recommendation 20 Rationale : The USPSTF found fair evidence that screening adolescents and adults not known to be at increased risk for HIV can detect additional individuals with HIV, and good evidence that appropriately timed interventions, especially HAART, lead to improved health outcomes for some of these individuals. However, the yield of screening persons without risk factors would be low, and potential harms associated with screening have been noted (above). The USPSTF concluded that the benefit of screening adolescents and adults without risk factors for HIV is too small relative to potential harms to justify a general recommendation." "The USPSTF recommends that clinicians screen all pregnant women for HIV. Rating: ‘A’ Recommendation 21 Rationale : The USPSTF found good evidence that both standard and FDA-approved rapid screening tests accurately detect HIV infection in pregnant women and fair evidence that introduction of universal prenatal counseling and voluntary testing increases the proportion of HIV-infected women who are diagnosed and are treated before delivery. There is good evidence that recommended regimens of HAART are acceptable to pregnant women and lead to significantly reduced rates of mother-to-child transmission. Early detection of maternal HIV infection also allows for discussion of elective cesarean section and avoidance of breastfeeding, both of which are associated with lower HIV transmission rates. There is no evidence of an increase in fetal anomalies or other fetal harm associated with currently recommended antiretroviral regimens (with the exception of efavirenz). Serious or fatal maternal events are rare using currently recommended combination therapies. The USPSTF concluded that the benefits of screening all pregnant women substantially outweigh potential harms." USPSTF Amendment (April 2007) "In September 2006, the Centers for Disease Control and Prevention (CDC) published revised guidelines recommending that all individuals between 13 and 64 years of age be screened for HIV regardless of recognized risk factors [ Branson 2006 ]. In making this recommendation, the CDC considered a number of factors, including research published subsequent to the completion of the systematic evidence report on which the 2005 HIV screening recommendations of the USPSTF are based. In November 2006, the USPSTF assessed this new research using established methods for evaluating the quality and strength of the evidence [Harris 2001]. Based on this review [Chou 2007], the USPSTF confirmed its ‘C’ recommendation for screening non-pregnant adolescents and adults who are not at increased risk for HIV infection." 22 USPSTF Grade Definitions Prior to May 2007 (parentheses and brackets are the USPSTF’s) "The U.S. Preventive Services Task Force (USPSTF) grades its recommendations according to one of five classifications (A, B, C, D, I) reflecting the strength of evidence and magnitude of net benefit (benefits minus harms). The USPSTF has updated its definition of the grades it assigns to recommendations. The definitions below (of USPSTF grades and quality of evidence ratings) were in use prior to the update and apply to recommendations voted on by the USPSTF prior to May 2007. ‘A’ – Strongly Recommended: The USPSTF strongly recommends that clinicians provide [the service] to eligible patients. The USPSTF found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms. ‘B’ – Recommended: The USPSTF recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms. ‘C’ – No Recommendation: The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation. ‘D’ – Not Recommended: The USPSTF recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits. ‘I’ – Insufficient Evidence to Make a Recommendation: The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that the [service] is effective is lacking, of poor quality, or conflicting and the balance of benefits and harms cannot be determined." 23 C. Literature Search In addition to the prerequisite USPSTF recommendations, CMS must consider not only whether an additional preventive service is reasonable and necessary for the prevention or early detection of illness or disability, but whether the service is appropriate for individuals entitled to benefits under part A or enrolled under part B of the Medicare program. To facilitate these determinations, we searched PubMed from 2004 to 2009 for clinical research studies, reviews and guidelines for HIV screening and disparities in older or elderly adults, as well as pregnant patients (to include disabled female Medicare beneficiaries < 65 years of age). Since most recent studies focused primarily on test characteristics – and have not considered outcomes such as survival – articles and reviews relating to HIV care and outcomes were also included. Studies of cost and cost-effectiveness were likewise included, as §1861(ddd)(2) expressly authorizes the agency to "conduct an assessment of the relation between predicted outcomes and the expenditures for such services". Studies must have been published in peer-reviewed English language journals, and abstracts were excluded. Using these general parameters, CMS identified one new clinical guideline (addressing both non-pregnant and pregnant individuals) plus 18 relevant articles and reviews. D. Discussion of evidence reviewed 1. Evidence Questions Our discussion focuses upon the adequacy of the evidence to draw conclusions about the risks and benefits of HIV screening for Medicare patients. CMS analyzed the following questions: Is the evidence sufficient to determine that HIV screening is recommended with a grade of A or B by the USPSTF for any indications? Is the evidence sufficient to determine that HIV screening is reasonable and necessary for the prevention or early detection of illness or disability? Is the evidence sufficient to determine that HIV screening is appropriate for Medicare beneficiaries? 2. External technology assessments and systematic reviews No new external technology assessment or systematic review was identified. 3. Internal technology assessment Winningham, et al. (2004) Winningham and colleagues, acknowledging that African-American women ≥ 50 years of age are disproportionately affected by the HIV/AIDS epidemic and account for > 65% of HIV cases among older women, conducted a cross-sectional survey (N = 181) in three rural South Carolina counties – using the AIDS Risk Reduction Model (ARRM) as a conceptual framework – and investigated HIV risk behavior among older rural African American women (mean age = 58 years; range = 50-81 years). Results showed most (67%) of the women had at least one sex partner in the past five years, and of those, more than half (59.5%) reported at least one sexual risk behavior. High-risk behavior was associated with less education, lower condom use self-efficacy, more peers who discussed HIV-related risk behavior and less comfort communicating with partners about sex. Winningham, et al. concluded that a significant proportion of older African American women living in rural counties are at increased risk for HIV infection; that delivering HIV prevention is challenging, particularly when the messages have to reach populations that do not believe they are at risk and therefore do not seek prevention services; and that integrating HIV prevention with other medical services already in place may be effective for this hard-to-reach older female population. 24 Burke, et al. (2007) Burke and colleagues conducted a review of both the published and unpublished literature on HIV testing barriers at the provider level and summarized their current understanding of why U.S. physicians do not offer HIV testing. The barriers identified in the studies were then summarized separately for the three practice settings and compared. Results identified 41 testing barriers in 17 studies; but many reviewed studies exhibited high refusal rates and there were substantial methodological limitations, low peer-reviewed publication rates, and (as noted by commenters) no references regarding survey reliability or validity. Eight testing barriers, i.e., insufficient time, burdensome consent process, lack of knowledge and/or training, lack of patient acceptance, pretest counseling requirements, competing priorities and inadequate reimbursement, were identified in all three settings (prenatal, emergency department and other medical settings). Burke, et al. concluded that physicians experience many policy-based (consent process, pretest counseling requirements and inadequate reimbursement), logistical (insufficient time, competing priorities and language barriers) and educational (lack of patient acceptance and lack of physician knowledge/training) barriers to HIV testing which included substantial overlap across different practice settings. 25 Espinoza, et al. (2007) Recognizing that a growing proportion of cases of heterosexually acquired HIV infections occur in women and in persons of color, Espinoza and colleagues retrospectively analyzed data from 29 states reporting confidential name-based HIV/AIDS cases to the CDC to calculate estimated annual percentage change in number of actual diagnoses, followed by multiple-variable logistic regression analysis to determine the association between race/ethnicity and whether diagnoses of HIV and AIDS were made concurrently – while adjusting for covariates which included delays in reporting and absence of information about HIV risk factors. Results showed that from 1999 to 2004 diagnoses of heterosexually acquired HIV were made for 52,569 persons in 29 states, of which 33,554 (64%) were women. Among men and women, 38,470 (73%) were non-Hispanic black; 7,761 (15%) were non-Hispanic white; and 5,383 (10%) were Hispanic. The number of persons with heterosexually acquired HIV significantly increased, including a 6.1% increase among Hispanic men (95% CI = 2.7, 9.7) and a 4.5% increase among Hispanic women (95% CI = 1.8, 7.3). Concurrent late HIV and AIDS diagnoses were slightly more common for non-Hispanic whites (23%) and Hispanics (23%) than for non-Hispanic blacks (20%), and the proportion of concurrent late HIV/AIDS diagnoses increased with age, which the authors posited may be explained by HIV disease progression tending to occur more rapidly in older persons or that older persons are not assumed to be at risk and therefore not the focus of testing programs. Espinoza, et al. concluded that, to decrease the incidence of heterosexually acquired HIV infections in particularly Hispanic and non-Hispanic black populations who historically have had less access to treatment and prevention services, new strategies are needed to remove barriers to access. Because concurrent late AIDS/HIV diagnoses imply missed opportunities for early treatment of HIV, the authors suggested facilitation of earlier diagnosis and entry into care to improve prognosis and survival rates; and that since access to HIV testing does not necessarily imply access to care, knowledge of HIV status be linked to care and treatment. 26 Ostermann, et al. (2007) Ostermann and colleagues, noting that increasing testing rates for groups not usually perceived as being at high risk has been advanced as a primary strategy to combat HIV, conducted a pooled cross-sectional data analysis of 146,868 participants aged 18-64 years in the 2000-2005 National Health Interview Surveys to determine trends in testing rates and differences between planned and actual testing across demographic and risk groups in the U.S. Multivariable logistic models were estimated to assess correlates of perceived risk for HIV, as well as for planned and actual HIV testing. Difference-in-differences models, said to cancel out biases that equally affected the compared groups, examined how differences between planned and actual testing varied with demographic characteristics, perceived risk, alcohol consumption, depression, health behaviors and access. Results showed that rates of testing remained relatively unchanged from 2000-2005 (mean rates for lifetime and past year, respectively, 37% and 10%), but that rates of HIV testing varied substantially by sex and race, with females and minorities (nonwhite) more likely to get tested. Rates were higher in individuals reporting greater risks of HIV infection, but among respondents reporting medium or high risks of contracting HIV, < 25% reported an HIV test in the previous year. Those with higher perceived HIV risk, more alcohol consumption and more depressive symptoms had higher rates of both planned and actual testing, but demonstrated the greatest deficit of actual testing versus planned testing. Ostermann, et al. concluded that testing rates in the U.S. remain low, both nationally and in high-risk populations; that low HIV testing rates contribute to a substantial number of undiagnosed cases of HIV; and that while compelling arguments are focused upon general population testing, considerable potential likely still exists to increase HIV testing rates in higher risk populations needing ensured access to and utilization of testing in alcohol and mental health treatment sites. 27 Owens, et al. (2007a) Owens and colleagues conducted a retrospective cohort analysis of 13,991 at-risk patients and evaluated practice patterns for HIV identification from 1995-2000 at four large VA health care centers having an estimated HIV prevalence ranging from 0.5-2.1%. The study reviewed 1,100 medical records of tested patients and assessed HIV testing rates for at-risk patients, rationale for HIV testing, and predictors of HIV testing and of HIV infection. Patients were defined at risk for HIV if records contained ICD-9 codes for substance use (alcohol, amphetamine, barbiturate, cannabis, cocaine, opioid, hallucinogen or other drug use, and unspecified and drug psychosis), hepatitis B, hepatitis C, all viral hepatitis (other than hepatitis B or C) or sexually transmitted disease at any visit during the study period. At the time when testing was performed, guidelines recommended risk-based testing; regulations required consent for testing and counseling; but documentation of consent and counseling was variable. Rationale for testing was documented if patients had an ICD-9 risk factor defined as above; if the provider documented a risk factor or clinical presentation suggestive of HIV, including opportunistic infection, hepatitis B, hepatitis C, or sexually transmitted diseases; or if the patient requested HIV testing. Sensitivity analyses used the most restrictive definition, including only cocaine, opiate or amphetamine use. Of 13,991 patients considered at risk for HIV, results showed that only 36% had been tested for HIV. The authors acknowledged being unable to determine whether patients had been tested in non-VA facilities or had been offered testing and refused, but considered it rare for patients to be tested elsewhere and refuse testing at the VA. HIV prevalence ranged from 1-20% among tested patients at the four sites, and 90% of patients tested had a documented reason to test. Owens, et al. concluded that one-half to two-thirds of patients identified at risk for HIV (based on ICD-9 diagnoses of substance abuse, hepatitis or sexually transmitted diseases) had not been tested for HIV within a five year period at the selected VA sites; noted that a critical opportunity to provide early therapy and risk-reduction counseling for HIV-infected patients may have been missed; questioned whether there are barriers to testing, including time required for informed consent and counseling; and while unable to determine which barriers were responsible for low HIV testing rates, believed that pretest and posttest counseling methods should be reexamined. 28 Gandhi, et al. (2007) Gandhi and colleagues conducted a retrospective observational study of HIV positive (N = 4368) patients entering HIV care from 1998-2002 at VA medical centers nationwide. Outcomes of interest were the AIDS rates in year of presentation, the duration of VA utilization before HIV presentation, and the presence of clinical triggers signaling greater risk of HIV infection before presentation. Results showed that 51% (N = 2211) of patients presented with CD4 counts < 200 cells/mm 3 ; and that 39% (N = 1697) of patients used other VA services before presentation for HIV care, with median duration of 3.6 years [interquartile range (IQR) 25–75: 2.2 to 5.1 year] and six physician visits (IQR 25–75: 2–18 visits) between first utilization and HIV presentation. No difference existed in the percentage of patients presenting with CD4 counts < 200 cells/ mm 3 in those with and without prior VA healthcare (50% versus 51%, P = 0.76), and only 13% of patients with prior VA healthcare demonstrated a clinical trigger before HIV presentation. Gandhi and colleagues concluded that more than half of veterans entered HIV care with an AIDS diagnosis at presentation regardless of whether they previously established healthcare in the VA; that access to care did not seem to be the primary cause of delayed HIV presentation; and that widespread screening is needed to improve rates of early HIV detection. 29 Owens, et al. (2007b) In 2007 Owens and colleagues additionally conducted a blinded, anonymous HIV serological survey (reported to be the preferred method for obtaining an unbiased prevalence estimate for a population) in order to determine HIV prevalence in both inpatient and outpatient settings of six geographically diverse VA healthcare sites. Sites were selected to represent the range within the VA of documented HIV prevalence – defined as number of HIV positive cases among patients with a documented negative or unknown test result. Logistic regression, including inpatient or outpatient status, age group, site, race/ethnicity and multiple comorbid conditions as independent variables, was utilized to determine predictors of documented and undocumented HIV infection. The study tested 4,500 unique outpatient blood specimens and 4,205 unique inpatient specimens, stratified into 5 age categories (25–44, 45–54, 55–64, 65–74, and 75 years or older) with ≥10% more than the required number of specimens for each group per the CDC’s recommendations for oversampling. A standard HIV-1 enzyme immunoassay (EIA) test was used to individually test all specimens; positive specimens underwent repeat EIA testing; and those positive after repeat testing underwent an HIV-1 Western blot confirmatory test. For study purposes, samples were defined as positive if positive according to both EIA and Western blot testing. Results showed that 326 (3.7%) patients tested positive for HIV. HIV prevalence ranged from 1.2-6.9% among inpatients and from 0.9-8.9% among outpatients; the percentage of HIV infections that had not been documented within the VA varied substantially between sites from 3-44%; and predictors of undocumented infection were age, race/ethnicity, site and history of pneumonia. Prevalence of previously undocumented HIV infection varied from 0.1-2.8% among outpatients and from 0.0-1.7% among inpatients. Compared to known HIV patients, undocumented HIV-infected patients were more likely older (> 55 years; P = 0.006) and less likely to have comorbidities (OR = 0.3; 95% CI = 0.15, 0.60; P < 0.001). For patients 65 -74 years of age with previous unknown test results, HIV prevalence was 0.5% (95% CI = 0.2, 1.2) for outpatients and 0.4% (95% CI = 0.1, 1.0) for inpatients. Owens, et al. concluded that prevalence of undocumented HIV infection was sufficiently high for routine screening to be cost-effective in each of the VA sites evaluated and that many VA health systems should consider expanded routine voluntary HIV screening. 30 Patterson, et al. (2007) Patterson and colleagues compared immunological reconstitution and virological response in the first six months of a first HAART regimen by both sex and age (≥ 50 versus < 50 years old) in two observational HIV-infected cohorts from the Johns Hopkins University and the University of North Carolina. A total of 246 individuals (28% women) were studied, with 63 cases (≥ 50 years old) and 183 controls (< 50 years old). Results showed that more than two-thirds of patients had HIV RNA levels < 400 HIV-1 RNA copies/mL and that CD4 count increased ≥ 50 cells/µL at six months from therapy initiation. There were no significant differences in immunological reconstitution across age and sex strata, or in virological suppression, even after adjusting for type of HAART or restricting the analysis to women only. Patterson, et al. concluded these results suggest that younger and older women and men may have similar short-term initial HAART outcomes, and that further evaluation of longer term response to initial HAART regimen based on sex and age is indicated with more efficacious and simplified regimens. 31 Silverberg, et al. (2007) Silverberg and colleagues reported on the growing, older adult, HIV-infected population’s response to and tolerability of highly active antiretroviral therapy (HAART). Changes in HIV clinical markers after HAART initiation were compared among 2259 patients aged 18-39 years (controls), 1834 patients aged 40-49 years and 997 patients ≥ 50 years enrolled in an integrated health care system. Results showed that patients ≥ 50 years were more likely to achieve HIV RNA levels of < 500 copies/mL within one year of HAART initiation (hazard ratio [HR], 1.15; P = 0.009), but adjustment for adherence attenuated this finding (HR, 1.03; P = 0.59). Subsequent HIV RNA level rebound to ≥ 1000 copies/mL was less likely among patients aged 40-49 years (HR, 0.81; P = 0.01), which persisted after adjustment for adherence (HR, 0.79; P = 0.004). In year one of HAART, younger patients had larger CD4 T-cell count increases (131.8, 121.3, and 111.8 CD4 T cells/µL per year among patients aged 18-39, 40-49 and ≥ 50 years, respectively; P = 0.046). In years 2-6, older patients had larger CD4 T-cell count increases (4.5, 11.6, and 9.7 CD4 T cells/µL per year among patients aged 18-39, 40-49 and ≥ 50 years, respectively; P = 0.04). After adjustment for adherence, age differences in CD4 cell count changes remained in year one (P = 0.02) but not in years 2-6 (P = 0.08). Comorbidities had no effect on study results, but metabolic (glucose and lipids), hematologic (absolute neutrophils and hemoglobin) and renal (creatinine) abnormalities were more likely in older patients. Silverberg, et al. concluded that, despite higher risk of adverse events, patients ≥ 50 years sustained high therapy adherence to maintain improved virological outcomes and compensate for early blunted CD4 cell count response as compared to younger patients. 32 Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group (2007) The DAD group is an international collaboration of 11 investigator groups prospectively following 23,437 HIV-1 infected individuals during outpatient clinic visits at 188 clinics in 21 countries in Europe, the U.S. and Australia since enrollment from December 1999-April 2001. Writing for DAD, Friis-Møller and colleagues analyzed the association of cumulative exposure to protease inhibitors (PIs) and nonnucleoside reverse-transcriptase inhibitors (NNRTIs) with the risk of myocardial infarction (MI) and reported on data collected through February 2005. Data including sociodemographics, clinical findings, treatment (antiretroviral and other medications received before and after enrollment) plus laboratory results were collected at enrollment and at least every eight months thereafter. Median age at enrollment was 39 years (IQR, 34-45 years) and 24.1% of patients were female. MIs were categorized and coded without knowledge of the patients’ ART history; incidence rates of MI during follow-up were calculated; and associations between MI and exposure to PIs or NNRTIs were determined. Results showed that 345 patients had an MI during 94,469 person-years of observation. The incidence of MI increased from 1.53 per 1000 person-years in those not exposed to PIs to 6.01 per 1000 person-years in those exposed to PIs for more than six years. When adjusted for exposure to the other drug class and known cardiovascular risk factors (excluding lipid levels), the relative rate of MI per year of PI exposure was 1.16 (95% CI, 1.10-1.23), whereas relative rate per year of exposure to NNRTIs was 1.05 (95% CI, 0.98-1.13). Adjustment for serum lipid levels reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04-1.18) and 1.00 (95% CI, 0.93-1.09), respectively. Friis-Møller, et al. concluded increased exposure to PIs is associated with increased risk of MI that is partly explained by dyslipidemia and found no evidence of association for NNRTIs, but the number of person-years of observation for exposure to NNRTIs was less than that for exposure to PIs. 33 Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group (2008) Since PIs are usually prescribed in combination with ART drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class and it was unclear whether NRTIs increase risk of MI in HIV-infected individuals, the DAD Study Group also used regression models to quantify the relationship between cumulative, recent and past use of zidovudine, didanosine, stavudine, lamivudine and abacavir and development of MI in 33,347 patients followed by investigators at 212 clinics in the DAD group. Results showed that over 157,912 person-years, 517 patients had an MI, but that there were no associations between rate of MI and cumulative or recent use of zidovudine, stavudine or lamivudine. By contrast, recent but not cumulative use of abacavir or didanosine was associated with an increased rate of MI, compared with those with no recent use of the drugs, RR 1.90, 95% CI 1.47–2.45 [P = 0.0001] with abacavir and RR 1.49, 1.14–1.95 [P = 0.003] with didanosine. Rates of MI were not significantly increased in those who stopped these drugs more than six months previously compared with those who never received these drugs. After adjustment for predicted ten year risk of coronary heart disease, recent use of didanosine and abacavir remained associated with increased rates of MI (1.49, 1.14-1.95 [P = 0.004] with didanosine; 1.89, 1.47-2.45 [P = 0.0001] with abacavir). The DAD study group concluded increased risk of MI exists for patients exposed to abacavir and didanosine within the prior six months, but that the excess risk did not seem to be explained by underlying established cardiovascular risk factors and was not present beyond six months after drug cessation. 34 Greenbaum, et al. (2008) Noting conflicting results in prior studies examining responses to HAART between younger and older patients, Greenbaum and colleagues performed a retrospective analysis of an observational cohort of 906 HAART-naïve patients enrolled from February 1989-January 2006. Virologic and immunologic response, plus progression to AIDS and mortality were compared in 670 younger patients (< 40 years) versus 149 older patients (≥ 50 years). To evaluate virologic suppression, HIV-1 RNA levels were used from all clinic visits following treatment initiation, and plasma HIV-1 RNA was categorized as undetectable (≤ 400 copies/ml) or detectable (> 400 copies/ml). Immunologic response was measured by change in CD4 cell count from baseline using cell count at HAART initiation and at 6, 12 and 24 months after treatment initiation; time to increase in CD4 cell count was days from HAART initiation to laboratory test date when the cell count had increased by 50 cells/ml or more; disease progression was examined as time to new opportunistic infections (OIs) after HAART initiation; and survival was analyzed based on the death registry database. Results showed that older rather than younger patients were more likely to be on nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens versus protease inhibitor (PI) regimens (42% versus 29%, P < 0.01). Time to HIV-1 RNA virologic suppression was less in older than in younger patients (3.2 versus 4.4 months, P < 0.01), but immunologic response did not differ by age. Older patients had fewer AIDS-defining OIs (22% versus 31%, P < 0.01) but higher mortality (36 versus 27%, P = 0.04) and shorter survival (25 th percentile survivor function 36.2 versus 58.5 months, P = 0.02) than younger patients. Older age was associated with more rapid virologic suppression [adjusted hazard ratio = 1.33 (1.09–1.63)] and earlier mortality [adjusted hazard ratio = 1.56 (1.14–2.14)]. NNRTI regimens had more rapid virologic suppression [adjusted hazard ratio = 1.22 (1.03-1.44)]. Greenbaum, et al. concluded that new studies were needed to examine long-term outcomes of HAART therapy – including impact of comorbidities on HIV disease progression, potential drug-drug interactions and potential differences in drug toxicity profiles in older adults – as well at that age-specific HIV treatment guidelines may be warranted which include HAART initiation at higher CD4 cell count for older patients. 35 Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group (2008) COHERE, a collaboration of 33 observational cohort studies in 30 European countries, followed 49,921 antiretroviral-naive individuals starting combination antiretroviral (cART) from 1998-2006. Outcome measures included the time from cART initiation to HIV RNA < 50 copies/ml (virological response) and CD4 increase of > 100 cells/ml (immunological response). Ten age strata were chosen: < 2, 2-5, 6-12, 13-17, 18-29, 30-39 (reference group), 40-49, 50-54, 55-59 and ≥ 60 years; and patients ≥ 6 years were included in multivariable analyses. The three oldest age groups had 2693, 1656 and 1613 individuals; and despite more advanced disease at treatment initiation (possibly due to later presentation for HIV care), results showed older patients were more likely than younger patients to demonstrate good initial virological response to cART. Specifically, the probability of virological response was higher in those aged 50–54 (adjusted hazard ratio: 1.24), 55–59 (1.24) and ≥ 60 (1.18) years. Probability, however, of immunological response was reduced in those ≥ 60 years, and patients 55–59 and ≥ 60 years had poorer clinical outcomes after adjusting for latest CD4 cell count. The COHERE group concluded that better virological responses but poorer immunological responses, together with low pre-cART CD4 cell counts, may place older patients at increased risk of HIV disease progression and other clinical events, including both traditional HIV-associated events as well as comorbidities that may occur more frequently in older individuals. 36 Strategies for Management of Antiretroviral Therapy (SMART) Study Group (2008) In a follow-on publication from El Sadr, et al’s 2006 SMART study demonstrating that episodic antiretroviral therapy (ART) guided by CD4 cell count did not reduce the risk of adverse events associated with ART, the SMART group in 2008 reported a comparison of two ART strategies – drug conservation (DC) and viral suppression (VS) – in 5472 HIV-infected patients with CD4 cell counts > 350 cells/µL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in the DC versus VS groups according to the latest CD4 cell count and HIV RNA level were reported. During follow-up (mean = 16 months), results showed that the DC patients spent more time with a latest CD4 cell count < 350 cells/µL (for DC versus VS, 31% versus 8%) and with a latest HIV RNA level > 400 copies/mL (71% versus 28%) and had higher rate of OD/death (3.4 versus 1.3/100 person-years) than VS patients. For follow-up periods with CD4 cell count < 350 cells/µL, rates of OD/death were increased but similar in the two groups (5.7 versus 4.6/100 person-years), whereas rates were higher in the DC versus VS patients (2.3 versus 1.0/100 person-years; RR 2.3 [95% CI, 1.5-3.4]) for periods with the latest CD4 cell count ≥ 350 cells/µL, an increase said to be explained by the higher HIV RNA levels in the DC group. The SMART group concluded higher risk of OD/death in DC patients was associated with more follow-up time with relative immunodeficiency, as well as living longer with uncontrolled HIV replication at higher CD4 cell counts; and that ongoing HIV replication at a given CD4 cell count placed patients at an excess risk of OD/death. The SMART group also concluded that, because deaths from causes other than OD dominate among HIV-infected patients receiving ART, the findings supported considering ART initiation before even moderate levels of immunodeficiency develop, though definitive information to guide such an approach awaits a new randomized trial [enrolling asymptomatic treatment-naïve patients] approaching the scale of SMART. 37 Lichtenstein, et al. (2008) Noting that U.S. clinical guidelines recommend deferring initiation of HAART for most patients with CD4 counts > 350 cells/mm 3 in part due to concerns about ART toxicity, Lichtenstein and colleagues analyzed incidence rates in the HIV Outpatient Study (HOPS) for three comorbidities (peripheral neuropathy, anemia and renal insufficiency) in multivariate Cox proportional hazards models by CD4 cell counts at HAART initiation. HOPS is an ongoing, prospective, cohort study of HIV-infected patients receiving care in nine participating HIV clinics in eight U.S. cities since March 1993. Within a total cohort of 2165 patients followed more than 3 years (mean), a neste